The first group of nutrient metals includes the most abundant of them—sodium, potassium, magnesium, and calcium. They function as regulators of osmotic pressure inside the cells and key regulators of biochemical processes (Fig. 1 and Fig. 2) [14].

The imbalance between intracellular and extracellular concentrations of sodium and potassium creates an electrochemical gradient or membrane potential that is a “vital force” for all living cells [15]. Membrane potential ensures the proper functioning of transmembrane transport enzymes, allowing passage of critical substances like glucose or Ca²⁺. High intracellular potassium concentration also facilitates the proper function of glycolysis, protein synthesis, and cell cycle progression [16].

The role of sodium and potassium in cancer was determined in the middle of the 20th century. While potassium promotes cancer from within the cells by inhibiting apoptosis, controlling the cell cycle, or changing cell shape, allowing metastasis [17,18], sodium acts in the extracellular environment, altering immune response [19] and the effectiveness of some weakly basic chemotherapeutic drugs like doxorubicin or vincristine promoting drug-resistant phenotypes of cancer cells. Prolonged treatment usually causes dysregulation of sodium or potassium metabolism in patients, resulting in hypernatremia or hypokalemia. These complications should be specifically addressed in order to avoid the development of more serious symptoms.

Calcium serves as a secondary messenger in numerous cellular signaling pathways [20]. The calcium release can trigger a variety of cellular responses, from changes in gene expression to metabolic shifts. The intake of the metal happens through numerous types of transporters, including non-selective ion channels, voltage-gated ion channels, and ligand-gated ion channels [21].

Magnesium is the most abundant divalent cation inside the cytoplasm. Its primary function is to serve as a cofactor for enzymes and “a shield” for negative charges on a variety of proteins. The absorption of Mg²⁺ is facilitated by 3 types of transporters: Mitochondrial RNA Splicing 2 (MRS2), Solute Carrier Family 41 (SLC41), and Transient Receptor Potential Melastatin 6/7 (TRPM6/7) transporters, which are hormonally regulated by insulin and epidermal growth factor. For intestinal intake, the intercellular transport conducted by claudin-2 and -12 is known. Some magnesium transporters can also transfer calcium ions through the membrane (but not vice versa) due to the similarities in hydrodynamic state and size. Magnesium is implicated in more than 600 enzymatic processes. It controls the proper work of ATP, mitochondria, the activity of vitamin D, and the elimination of oxidative stress [22].

These two metals play a key role in the formation, development and spread of cancer. Since calcium signaling is a crucial regulator of numerous processes involved in cell growth, some tumors (gliomas, breast, colorectal, prostate cancers, etc.) exhibit an increased expression of calcium transporters—TRPC, TRPM family, VGCCs [20]. This stimulates intracellular signaling that promotes activation of key pro-survival and growth factors (NFAT, NF-kB, c-Myc). These processes are well-characterized for prostate cancer, where calcium can promote cell survival and even participate in the formation of drug resistance [23]. The particular role of magnesium in cancer is still ambiguous. On the one hand, its increased consumption is linked to decreased risks of colon cancer in women, on the other—a positive correlation between high magnesium and breast cancer was also determined [24]. In a study on cultivated cancer cells, it was revealed that they indeed tend to accumulate more Mg²⁺ ions, which is explained by increased ATP demands [25]. However, in vivo studies indicate that low magnesium can simultaneously support and limit cancer burden [26]. So, for now, magnesium appears as a double-edged sword in cancer since it can either stimulate or inhibit its growth depending on the conditions and model used.

Thus, essential biogenic metals play a huge role in normal cell physiology and act as important factors in cancer development and progression. They can promote malignant cell growth or suppress it, depending on the conditions, which should be carefully considered by clinicians.

Transition elements such as iron, copper, manganese, cobalt, molybdenum, nickel and post-transition metal zinc are important trace elements that play diverse roles in the cell, being catalytic and, mostly for Zn, structural co-factors [27]. Fe and Cu are typical redox-active metals, which participate in Fenton-like reactions, while Mn, Co, Mo, Ni are less involved in oxidation-reduction reactions, and Zn is redox-inert. All of them are prone to form coordination complexes, such as zing fingers, heme, cobalamin (vitamin B12) and molybdenum cofactor (MoCo).

All mentioned trace elements, while maintained under homeostatic control, play vital roles in the human body. Most of the iron is utilized in the bone marrow for the synthesis of hemoglobin and red blood cells. Besides, iron is distributed to peripheral tissues through the bloodstream, where it is necessary for DNA synthesis, cell cycle progression, energy generation, heme synthesis, and the formation of iron-sulfur (Fe-S) clusters [28]. Zinc is necessary for the functioning of approximately 10% of the mammalian proteome, which contains zinc-binding domains, primarily zinc fingers [29]. These structures enable interactions with various biomolecules, including nucleic acids and other proteins, allowing zinc to regulate essential cellular processes such as DNA synthesis, gene regulation, enzymatic catalysis and apoptosis [30]. Moreover, zinc(II) ions play a signaling role, participating in phosphorylation and redox processes, and acts like an antioxidant by being a component of antioxidant proteins (for example, superoxide dismutase 1 (SOD1)) and metallothioneins [31]. Manganese is critically involved in energy metabolism by activating pyruvate carboxylase, isocitrate dehydrogenase, and glycosyl transferase, an enzyme required for mucopolysaccharide production. Also, there is a specific group of enzymes, vital specifically for the function of neurons and glial cells, while also playing roles in other tissues, which exhibits a strict dependence on Mn: superoxide dismutase 2, glutamine synthetase, arginase, pyruvate decarboxylase, and serine/threonine phosphatase [32]. Сopper is the critical cofactor of cytochrome-c-oxidase, influencing the mitochondrial electron transport chain, and is required for the activity of SOD1, same as Zn. Additionally, copper is essential for iron uptake and homeostasis, acting as a cofactor for ferroxidases like ceruloplasmin and hephaestin, which facilitate iron transport and prevent anemia [33]. Nickel is a component of essential enzymes like urease, hydrogenase, s-methyl coenzyme-M reductase, acetyl CoA synthase, CO dehydrogenase, Ni-superoxide dismutase, glyoxalase 1, and cis–trans isomerase. In parallel, molybdenum is central to the function of enzymes like xanthine oxidase and sulfite oxidase, crucial for purine metabolism and detoxification [34]. Cobalt is uniquely required as a core component of the cobalamin (vitamin B12), which is vital for DNA synthesis and neurological function.

Free ion concentration of these metals under normal conditions is low because their homeostasis is controlled by metal-binding and transporting proteins. The control begins when a metal enters the cell via specific influx systems: divalent metal transporter 1 (DMT1) for the majority of metals, the transferrin (TF)-transferrin receptor (TFR) complex for Fe and Mn, ZIP proteins (SLC39A) for Zn and Mn, calcium channels for Mn, Co and Ni [35], and copper transporter 1 (CTR1) for Cu. Molybdenum may decrease copper bioavailability by forming complexes with it or competing for uptake via transporters, while zinc and nickel may also act antagonistically [36,37]. After entry, in order to prevent an increase in free ion concentration, metals are bound by specific proteins, which are called metallothioneins (MTs). Moreover, glutathione is also able to bind various metals, while ferritin specifically sequesters iron, Atox1 and some other chaperones—copper. Excessive amounts of ions are exported by particular transporters: ferroportin (FPN) for Fe and Mn, ZnT transporters (SLC30A) for Zn, and ATPases ATP7A/B for Cu [32,37].

Metal Regulatory Transcription Factor 1 (MTF1) is primarily involved in controlling cadmium, zinc, and copper concentration in the cell. MTF1 serves as a transcription factor for metal-dependent proteins involved in cell and tissue development in accordance with the blood system. Ultimately, MTF1 is regulated by the cellular presence of the respective metal ions and stress conditions, including insufficient blood supply. It makes MTF1 one of the key genes responsible for tumor-associated angiogenesis and a target for further therapy approaches.

Dysregulation of metal levels often occurs in cancer, which frequently involves an increase in the labile pool of ions within the cell, resulting from impaired function of metal transporters or metal-binding antioxidant proteins. Free ion overload may lead to the excessive production of ROS, which further promotes carcinogenesis. This occurs primarily through the Fenton and Haber-Weiss reactions (•O₂⁻ + H₂O₂ → •OH + OH⁻ + O₂) in the presence of iron and copper ions.

Cobalt, molybdenum, and nickel also facilitate ROS generation andinduce mutations in genes like KRAS, EGFR, and TP53, and by replacing magnesium ions in heterochromatin, causing its decondensation and subsequent chromosomal aberrations, respectively [35,36]. Manganese lacks Fenton activity and may competitively inhibit iron, but at the same time, its accumulation associates with poor prognosis in glioblastoma/melanoma and promotes migration via exosomal transport [38]. Similar to manganese, redox-inert zinc can inhibit Fenton chemistry by displacing redox-active ions from critical membrane sites, thereby preventing ROS formation [39]. Thus, zinc differs from the aforementioned metals, as its deficiency, rather than overload, is more commonly observed in cancer, especially esophageal [40]. Nevertheless, any dysregulation of zinc homeostasis can influence cancer development and progression by supporting cancer cell growth and survival, altering their sensitivity to apoptosis [39,40].

Enzymes regulating metal homeostasis and molecular targets of important signaling pathways are critically involved in cancer pathogenesis, with distinct roles in metastasis and multi-drug resistance (MDR). Pro-tumorigenic iron accumulation is driven by increased transferrin receptor 1 (TFR1) and hepcidin (which downregulates the exporter ferroportin (FPN1)), with alternative iron transport through increased lipocalin 2 (LCN2), which promotes metastasis and invasion, also inhibiting apoptosis [41]. Similarly, aberrant zinc homeostasis enhances cancer invasiveness and MDR. High metallothionein expression promotes MDR by sequestering chemotherapeutic drugs, neutralizing ROS, and donating zinc to transcription factors, while upregulated zinc transporters like ZIP7 hyperactivate growth pathways (such as EGFR, HER2) and ZIP10 enhances cell migration [42]. Stress-induced zinc release from zinc-finger motifs alters NF-κB, p53, and AP-1 activity to promote survival, and zinc finger transcription factors (for instance, Snail, ZEB) drive MDR by enhancing ABC transporter gene expression [43]. Manganese contributes to invasion by activating SOD2 in order to increase mitochondrial oxidative stress and by modulating epigenetic regulation through histone acetyltransferase (HAT) suppression and histone deacetylase (HDAC) activation [38]. Copper-dependent enzymes like MEK1, SOD1, COX, LOX participate in tumor growth and metastasis, and copper overload promotes MDR through reduced drug intake via lower CTR1 expression, impaired DNA repair via Atox1-induced expression of MDC1, and elevated drug efflux via ATP7A [44]. Cobalt overload supports cancer cells’ proliferation and angiogenesis via the stabilization and subsequent high activity of hypoxia-inducible factor 1 (HIF-1) [45].

Most metals of this group are often referred to as “heavy metals” due to their high atomic weight. Their presence inside the cells and the organism as a whole is minor, however, they still can have some specific function in biochemical pathways or be poisonous and toxic, which is a more common case.

Typically known poisonous and carcinogenic heavy metals include arsenic, cadmium, lead, mercury, and chromium (VI). Their carcinogenic mechanism involves prolonged oxidative stress caused by chronic ROS production via binding to thiol groups, displacement of essential metals, disruption of antioxidant defenses, DNA damage, and mitochondrial dysfunction [46,47]. Specifically, arsenic predominantly generates superoxide and hydrogen peroxide radicals, causing single- and double-strand DNA breaks and the formation of DNA adducts [46,48]. Cadmium mainly acts by binding to thiol groups of antioxidant enzymes and inducing lipid peroxidation, leading to oxidative stress without direct ROS generation [49]. The primary toxic effect of lead is the depletion of the cellular antioxidant pool, particularly glutathione (GSH) [50]. Mercury inhibits selenoenzymes, such as thioredoxin reductase, which are critical for maintaining antioxidant defenses [51]. Although the trivalent chromium form is essential, the hexavalent one is toxic to the cell. The key source of its toxicity is the reduction of Cr(VI) to Cr(III), resulting in hydrogen peroxide and other ROS generation [52].

Besides mentioned, there are inert metals, such as Au, Pt, Ir, and Ru, free ions of which are not typically prevalent in cells, but compounds with such elements exhibit toxic effects toward cancer cells.

The high activity and importance of alkali and alkaline earth metals for all living cells, as well as the prevalence and similarity of the metabolism of these metals in normal and tumor cells, make it difficult to develop stable drugs based on sodium, potassium, calcium or magnesium [54]. However, these elements have found their application in cancer therapy as modulators of antitumor response or supportive treatment that helps alleviate the symptoms or adverse effects of the main course of chemotherapy, e.g., dyselectrolytemias [55].

While most drug molecules exist as sodium or potassium salts, the ions in this case do not possess any therapeutic activity but rather serve as a counterion, hedging critical functional groups. Due to its activity, sodium is not properly accountable for creating stable coordinating complexes or nanoparticles. Represented sodium drugs, including mostly metabolite counterparts, like methotrexate sodium or talaporfin sodium [56], and specific nanostructures, like sodium selenite [57].

Potassium acts similarly to sodium, enhancing drug solubility as a counterion in compounds like potassium oxonate or potassium quercetin-5′-sulfonate. The element has also found its application in the stimulation of the immune system and combined modalities with immunotherapy [58].

That cannot be said about calcium-based compounds, whose major advantage is their full physiological biocompatibility, stability, and biodegradability. One of the crucial directions in calcium-based therapeutics is the development of pH-responsive nanomaterials for targeted delivery [59]. Calcium phosphates, calcium carbonates, calcium silicate, and calcium fluoride are widely utilized for these purposes. Various forms of CaX NPs are now under research or development [59,60]. These materials can be applied for the treatment of various types of cancer, including breast and prostate types [61]. Major concerns regarding calcium-based therapeutics and treatment modalities are systemic toxicity (for nanoparticles), variability in calcium channels expression profile, and rapid clearance due to high biocompatibility [62].

In many aspects, magnesium shares the properties of calcium. Its usage is also concentrated on the magnetic alloys, pH-responsive nanomaterials and nanoparticles [63]. The advantages of Mg-based therapeutics include their high biocompatibility and biodegradability, while concerns mainly concentrate around the high reactivity of the metal, its dual role in cancer (see above), and limited data from clinical trials [64]. For manganese, there are also several nanosystems that are currently under development for the treatment of cancer of various origins, particularly breast and lung cancer [65]. Some works also describe current efforts to develop Mg-based nanomaterials for the delivery of anticancer drugs and their targeted release [66].

It is worth noticing that ion channels for all elements of this group are actively studied as a suitable target for cancer treatment. These compounds are not metal-based per se, but they possess the activity allowing them to alter the intracellular transport of critical ions. There are numerous pharmacological substances targeting sodium [67], potassium [68], or calcium [69] ion channels. The opposite group of compounds are often called ionophores since they are able to bind metal ions allowing their alleviated transport across the plasma membrane. This process increases the concentration of metal ions inside the cell that results in overload and disruption of critical processes [70]. These two classes of drugs while beyond the scope of this review attract ultimate research interest in recent years.

Elements from group 3 historically were the most used in cancer treatment, with cisplatin (and platinum-based drugs) being the best known and widely applicable substance suitable for a variety of clinical cases. The major obstacle in utilizing elements of this group and drugs based on their basis is the lack of biocompatibility and biodegradability, which often results in side effects that can last for years [112,113]. Heavy elements cannot be incorporated in natural biochemical circuits, which leads to their accumulation in various sites, usually bones, kidneys, liver, and brain. Nevertheless, unique properties of the elements of this group make them indispensable for the development of anticancer drugs even beyond classic cytotoxic substances. New therapeutic modalities include formulations for theranostics allowing real-time controlled treatment of malignancies. A lot of elements of this group have found their application in radiotherapy, because heavy elements usually have several unstable isotopes that are a perfect match for the treatment or diagnostic purposes [114]. Below, we will emphasize the progress made in the development of therapeutic formulations based on specific elements that currently have (or might have in the future) the biggest potential in the field.

Beyond discrete complexes and nanoparticles, metal-organic frameworks (MOFs) represent a frontier in inorganic-organic hybrid materials, functioning as reactive and functional polymers with precisely engineered porosity and composition [133]. Their crystalline structure, built from metal-ion nodes (e.g., Fe, Zn, Cu, Zr, Mn) and organic linkers, creates a versatile platform for cancer theranostics. A key advantage is their high surface area and tunable chemistry, which enables exceptional drug loading and stimuli-responsive release within the tumor microenvironment (TME). For instance, zeolitic imidazolate framework-8 (ZIF-8), a Zn-based MOF, is stable at physiological pH but rapidly degrades in acidic tumor microenvironment, releasing encapsulated chemotherapeutics with high specificity [134,135]. Similarly, Fe-based MOFs (e.g., MIL-100) and Cu-based MOFs (e.g., HKUST-1) not only deliver drugs but also act as intrinsic nanozymes, catalyzing the conversion of tumor H₂O₂ into cytotoxic hydroxyl radicals via sustained Fenton reactions for potent chemodynamic therapy (CDT) [136]. More advanced theranostic designs incorporate imaging agents; Zr-based MOFs (e.g., UiO-66) loaded with gadolinium or radioisotopes can provide contrast for MRI or act as radiosensitizers while delivering therapeutic payloads [137]. Despite their promise, challenges such as controlled biodegradation, long-term in vivo stability, and scalable synthesis remain active areas of investigation [133].

Chemoresistant cells rewire central metabolism to neutralize oxidative injury, sustain biosynthesis, and stabilize energy supply. Upregulation of the pentose phosphate and one-carbon pathways elevates NADPH and dNTP reserves, quenching drug-induced ROS and attenuating antimetabolites, while expansion of glutathione and thioredoxin networks detoxifies electrophiles and preserves the thiol proteome. In parallel, a shift toward mitochondrial OXPHOS and fatty-acid oxidation sustains ATP and redox balance under mitotic and replication stress, and lipid remodeling limits membrane peroxidation, further diminishing cytotoxic impact. Metal-based agents can invert these protective adaptations by exploiting redox and thiol abundance as activation cues and by directly disabling mitochondrial function. Gold complexes inhibit thioredoxin reductase [183,189], copper and iron complexes deplete glutathione to induce oxidative stress and inhibit glutathione peroxidase 4 (GPX4) [180,182], and mitochondria-targeted Pt(IV)/Ru chemotypes collapse respiration [190]. By converging on OXPHOS, glycolysis, and the Trx axis, these agents also constrain the metabolic plasticity of cancer stem cells, undermining lineage-specific resistances and impairing survival and self-renewal.

Across tumor types, resistant cells rechannel signaling through PI3K–AKT–mTOR, RAS–ERK, Hippo–YAP/TAZ, and STAT3/NF-κB axes, while stress-adaptive nodes (HIFs, NRF2, AMPK, UPR) stabilize redox balance, nutrient acquisition, and lipid anabolism [191,192,193]. Metal-based agents have emerged as multipronged tools to intercept these adaptations.

Drug resistance driven by enhanced DNA repair is a major barrier to effective cancer therapy, particularly for non-metal-based drugs such as antimetabolites, topoisomerase inhibitors, and targeted agents.

Non-metal-based chemotherapeutics (e.g., 5-fluorouracil, doxorubicin, temozolomide paclitaxel, and targeted kinase inhibitors) often fail due to cancer cells’ upregulation of DNA repair mechanisms: nucleotide excision repair (NER), homologous recombination (HR), base excision repair (BER), and others [208]. For example, resistance to 5-FU and doxorubicin is frequently associated with elevated DNA repair capacity, while PARP inhibitor resistance can arise from restoration of HR function [209].

High copper levels can activate nuclear copper chaperones (e.g., ATOX1), which in turn regulate DNA repair proteins such as MDC1 related to HR/NHEJ mechanisms. Targeting this axis sensitizes resistant tumors to genotoxic drugs [210]. Another effective way to handle enhanced DNA repair is to target mitochondrial DNA (mtDNA) by copper, iridium and ruthenium-based compounds [164,211]. Unlike nuclear DNA, mtDNA lacks a nucleic acid excision repair pathway and histone protection, making it more susceptible to damage. Complexes based on Mn and temozolomide (TMZ) are capable of significantly increasing damage to DNA by also downregulating the expression of MGMT, which repairs DNA lesions after sole temozolomide (TMZ) treatment in glioblastoma. Manganese nanoparticles produce O2 and ROS that downregulate enhanced DNA repair dependent on MGMT, which is crucial in the glioblastoma model [188].

Developing compounds with a multitargeting approach became one of the strategies, especially as the next generation of platinum-based drugs, which were previously highly susceptible to enhanced DNA repair systems. Pt(IV)-based mononitro-naphthalimide conjugate not only induces severe DNA damage higher than that of cisplatin, but also inhibits the repair processes, specifically by down-regulating the RAD51 protein, which is crucial for homologous recombination (HR) and repair of DNA double-strand breaks [212]. Platinum nanozymes induce both DNA platination and oxidative cleavage, disrupting the DNA bending required for NER and preventing repair of platinum-DNA adducts, thus overcoming resistance even in NER-proficient cells [213]. PARP and HDAC inhibitors as ligands in platinum(IV) complexes showed high cytotoxicity in triple-negative breast cancer and glioblastoma cells, disrupting enhanced DNA repair mechanisms, including PARP and BAP, impairing antioxidant defenses, and prolonging cell cycle blockade [208,214].

The tumor microenvironment (TME) comprises interdependent cellular (reprogrammed fibroblasts and immune cells) and acellular components (hypoxia, pH, and extracellular matrix (ECM)) that collectively limit the efficacy of cytotoxic chemotherapies, targeted small-molecule inhibitors, and monoclonal antibodies. Several hallmark features of the TME converge to reduce drug delivery, alter drug metabolism, and induce adaptive resistance programs in cancer cells. On the contrary, metal compounds are able to effectively circumvent some obstacles associated with the tumor microenvironment.

Hypoxia arises from disorganized, leaky, and poorly perfused vessels, promoting genetic instability and pro-angiogenic signaling that further lead to vascular abnormality. Hypoxia reprograms tumor metabolism toward glycolysis and redox plasticity, increases glutathione and NADPH buffering, upregulates drug-efflux transporters (e.g., ABC family), and fosters epithelial–mesenchymal transition and stem-like states that better tolerate DNA damage and apoptotic signals. These changes blunt the activity of DNA-damaging chemotherapies, many kinase inhibitors, and antibody therapeutics that rely on adequate perfusion for delivery. Metal-based compounds are able to withstand hypoxia in several ways. Firstly, metal peroxide nanoparticles (e.g., manganese TMZ@HMnO2@PDA-PEG-RAP12 and calcium peroxides) react with the acidic tumor environment to generate oxygen, alleviating hypoxia and sensitizing tumors to therapy. This oxygen release can restore the efficacy of oxygen-dependent treatments and reduce HIF-1α-mediated resistance pathways [188]. Secondly, the hypoxic environment can be a selective target for some metal-based drugs (e.g., HA-CuMOF@DOX and CuGI@CM) [182,187]. Thirdly, the hypoxia can be deregulated through the inhibition of cell signaling, PI3K/AKT, STAT-3.

Cancer-associated fibroblasts (CAFs) deposit and crosslink collagen and hyaluronan, stiffening and densifying the ECM, compressing vessels, and establishing steep gradients of oxygen, pH, and nutrients. The resulting elevated interstitial fluid pressure and tortuous diffusion paths impede penetration of small molecules and especially large biologics (mAbs, ADCs). CAF-derived cytokines and growth factors (e.g., IL-6, TGF-β, HGF) provide parallel survival cues that reduce dependence on the intended drug target and promote reversible drug tolerance. Au@Ag and AgNPs inhibit the cancer-promoting activity of CAFs by modulating their secretory profiles and altering their interaction with cancer cells. They also reduce the expression of genes related to cancer invasion and metastasis, such as secreted phosphoprotein 1 (Spp1, which encodes osteopontin), pleiotrophin (Ptn), thrombospondin 2 (Thbs2), and ADAM metallopeptidase with thrombospondin type 1 motif 5 (Adamts5) [215]. Disulfiram/copper (DSF/Cu) induces apoptosis and necrosis in both cancer cells and α-SMA-positive CAFs. It downregulates CAF activation markers (α-SMA, FAP-α), functionally inactivating CAFs and reducing their tumor-supportive activity [216].

Tumor-associated macrophages, neutrophils, and myeloid-derived suppressor cells create an immune-privileged niche by supplying growth and survival factors, scavenging reactive oxygen species, remodeling the ECM, and expressing checkpoint ligands that blunt cytotoxic T-cell activity. Therapy itself can reinforce these programs by inducing senescence-associated secretory phenotypes and wound-healing signals. Such myeloid-driven circuits can limit the efficacy of mAbs that require Fc-mediated effector functions, attenuate immunogenic cell death from chemotherapy, and provide bypass signaling that undermines targeted inhibitors. Drugs based on iron and copper, or containing both metals simultaneously, have shown the ability to prevent low immunogenicity in tumor environments by inducing ferroptosis and cuproptosis. These drugs can repolarize tumor-associated macrophages (TAMs) from the M2 phenotype to the M1 phenotype, increase intratumoral infiltration of CD8⁺ cytotoxic T lymphocytes and natural killer cells, which has an antitumor effect [163,164]. Copper-deposited metal-phenolic networks (TAF-CuET), Manganese Nanoparticles and Pt-conjugates are also capable of reducing the fraction of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and activating cytotoxic T lymphocytes [165,217].

Extracellular vesicle transport from resistant cancer cell lines to susceptible ones was reported as a problem for TKI treatment. Transported SLC-transporters (SLC1A5 and SLC25A5) activated metabolism change to OXPHOS in cancer cells and immunosuppression of tumour microenvironment (polarization of macrophages to M2 and inhibition of dendritic cell function) [218]. This description creates good initial conditions for further research regarding the use of metal-based compounds.

Metal nanoparticles (MNPs), as briefly mentioned above, represent one of the most famous fast-developing and frequently used forms of metal-based therapeutics. In previous sections, we were mostly focused on the pure mono-metal nanoformulations, while there are numerous attempts to create complex nanosystems with interesting properties and biological activity. This vast field of research is beyond the scale of this article so here we mention only several important trends that we consider necessary additional attention in the context of this review.

The first trend is the creation of multi-metal NPs, that can be in a form of polymetallic alloy or a more complex multilayered structure. These formulations can combine unique properties of several metals. For example, multifunctional MNPs with a combination of iron and noble metals (silver, gold, or platinum) acquire magnetic properties with simultaneously higher stability, lower reactivity, and tuned optical properties (plasmon resonance), which enables multimodal imaging [219]. Gold-copper alloys possess enhanced catalytic and photo-optic properties [220], which found their use in cancer theranostics [221].

The second major tendency is the creation of sophisticated organic coatings and the application of drug payloads for precise targeting. This process radically changes the physico-chemical properties of NPs as well as their biological behaviour and activity. MNPs can be modified with small organic molecules, polyorganic shells, biomolecules (nucleic acids or proteins), and other types of coagulants [222]. Each modification brings a new feature to the nanosystem, for example, polyethylene glycol (PEG) is used for shielding active metal core from the surroundings [223], folic acid targets NPs toward cancer cells overexpressing folate receptors [224], hyaluronic acid and other polymers for drug delivery [225], chitosan improves NPs stability and delivery capacity [226]. Moreover, important modifiers are antibodies and polypeptides, which can be designed to target specific cells or suppress specific molecular targets [227]. Although these biomodifications really widen the spectrum of possible applications of NPs, the concern over immunogenicity and toxicity still remains.

Overall, we can expect major breakthroughs in the field of functionalized metal-based nanoparticles and approvals from the FDA for their use in many fields, including cancer diagnosis and treatment. Current solutions gravitate around various types of coatings and shells with simultaneous experiments with a metallic core, which combined make the number of possible solutions and formulations almost infinite.

To illustrate the translational potential of metal-based nanoparticles in overcoming MDR, Table 4 summarizes representative in vitro and in vivo studies. These examples highlight how MNPs can bypass efflux pumps, modulate the tumor microenvironment, induce novel cell death pathways, and synergize with existing therapies to resensitize resistant cancers.

Some modern concepts of future drug therapy propose combining several therapeutic modalities into one system in order to address different aspects of tumor progression and the immunosuppressive tumor microenvironment (TME). One study proposes a therapy that includes photothermal, chemodynamic therapy, and immunomodulation caused by copper ions (Cu²⁺), in combination with an anti-PD-L1 antibody and S-nitrosoglutathione (GSNO), for the regulation of cancer-associated fibroblasts on a hydrogel platform that controls the release of compounds [230].